Human temperature regulation under heat stress in health, disease, and injury.

The human body constantly exchanges heat with the environment. Temperature regulation is a homeostatic feedback control system that ensures deep body temperature is maintained within narrow limits despite wide variations in environmental conditions and activity-related elevations in metabolic heat production. Extensive research has been performed to study the physiological regulation of deep body temperature. This review focuses on healthy and disordered human temperature regulation during heat stress. Central to this discussion is the notion that various morphological features, intrinsic factors, diseases, and injuries independently and interactively influence deep body temperature during exercise and/or exposure to hot ambient temperatures. The first sections review fundamental aspects of the human heat stress response, including the biophysical principles governing heat balance and the autonomic control of heat loss thermoeffectors. Next, we discuss the effects of different intrinsic factors (morphology, heat adaptation, biological sex, and age), diseases (neurological, cardiovascular, metabolic, and genetic), and injuries (spinal cord injury, deep burns, and heat stroke), with emphasis on the mechanisms by which these factors enhance or disturb the regulation of deep body temperature during heat stress. We conclude with key unanswered questions in this field of research.

Conversion to Radical Nephrectomy From Robotic Partial Nephrectomy Is Most Commonly Due to Anatomic and Oncologic Complexity.

PURPOSE: Partial nephrectomy is standard-of-care treatment for small renal masses. As utilization of partial nephrectomy increases and includes larger and complex tumors, the risk of conversion to radical nephrectomy likely increases. We evaluated incidence and reason for conversion to radical nephrectomy in patients scheduled for partial nephrectomy by surgeons participating in MUSIC (the Michigan Urologic Surgery Improvement Collaborative). MATERIALS AND METHODS: All patients in whom robotic partial nephrectomy was planned were stratified by completed procedure (robotic partial nephrectomy vs radical nephrectomy). Preoperative and intraoperative records were reviewed for preoperative assessment of difficulty and reason for conversion. Patient, tumor, pathologic, and practice variables were compared between cohorts. RESULTS: Of 650 patients scheduled for robotic partial nephrectomy, conversion to radical nephrectomy occurred in 27 (4.2%) patients. No conversions to open were reported. Preoperative documentation indicated a plan for possible conversion in 18 (67%) patients including partial with possible radical (n = 8), partial vs radical (n = 6), or likely radical nephrectomy (n = 4). Intraoperative documentation indicated that only 5 (19%) conversions were secondary to bleeding, with the remaining conversions due to tumor complexity and/or oncologic concerns. Patients undergoing conversion had larger (4.7 vs 2.8 cm, P < .001) and higher-complexity tumors (64% vs 6%, P < .001) with R.E.N.A.L. (for radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry score ≥ 10. The converted cases had a higher rate of ≥ pT3 (27% vs 8.4%, P = .008). CONCLUSIONS: There was a low rate of conversion from robotic partial to radical nephrectomy in the MUSIC-KIDNEY (Kidney mass: Identifying and Defining Necessary Evaluation and therapY) collaborative, and an even lower risk of conversion due to uncontrolled bleeding. Targeted review of each conversion identified appropriate decision-making based on oncologic risk in most cases.

Plasma epinephrine and norepinephrine responses to extreme heat exposures in young and older adults.

Hyperthermia is known as a hyperadrenergic state, yet there is a lack of data on the sympathetic responses to ambient heat stress in humans. Therefore, we investigated the plasma epinephrine and norepinephrine concentrations of healthy young and older adults exposed to 3 h of very hot and dry, as well as hot and humid, heat, both with accompanying activities of daily living. We hypothesized that older adults, compared with young adults, would have augmented increases in epinephrine and norepinephrine concentrations secondary to increased thermal strain. Young (n = 20) and older (n = 18) participants underwent two 3-h heat exposures on different days: very hot and dry [47°C and 15% relative humidity (RH)] and hot and humid (41°C and 40% RH). To mimic heat generation comparable to activities of daily living, participants performed seven 5-min bouts of light cycling (approximately 3 METS) dispersed throughout the heat exposure. We measured plasma concentrations of epinephrine and norepinephrine at baseline, end, and 2-h postheat exposure. There was a group-wide increase in epinephrine from baseline to the end of the heat exposure (Δ19 ± 27 pg/mL; P < 0.001) in the hot and humid condition, but not in the very hot and dry condition (Δ6 ± 19 pg/mL; P = 0.10). There were group-wide decreases in norepinephrine concentrations from baseline to the end of the heat exposure in both the very hot and dry (Δ-131 ± 169 pg/mL; P < 0.001) and the hot and humid (Δ-138 ± 157 pg/mL; P < 0.001) conditions, with both returning to near baseline at 2-h postexposure. These data suggest that ambient heating with accompanying bouts of light intermittent exercise may lead to decreases in circulating concentrations of norepinephrine.NEW & NOTEWORTHY Herein we present plasma epinephrine and norepinephrine concentrations to 3 h of very hot and dry, as well as hot and humid, heat exposures with accompanying activities of daily living in young and older participants. We found 1) increased plasma concentrations of epinephrine in young and older adults following the hot and humid, but not the very hot and dry exposures and 2) decreased concentrations of norepinephrine in both groups following exposure to both conditions.

Low-dose sufentanil does not affect tolerance to LBNP-induced central hypovolemia or blood pressure responses during a cold pressor test.

Hemorrhage is a leading cause of death in the prehospital setting. Since trauma-induced pain often accompanies a hemorrhagic insult, the administered pain medication must not interfere with critical autonomic regulation of arterial blood pressure and vital organ perfusion. The purpose of this study was to test two unrelated hypotheses: 1) sublingual sufentanil (Dsuvia) impairs tolerance to progressive central hypovolemia and 2) sublingual sufentanil attenuates pain sensation and the accompanying cardiovascular responses to a noxious stimulus. Twenty-nine adults participated in this double-blinded, randomized, crossover, placebo-controlled trial. After sublingual administration of sufentanil (30 µg) or placebo, participants completed a progressive lower-body negative pressure (LBNP) challenge to tolerance (aim 1). After a recovery period, participants completed a cold pressor test (CPT; aim 2). Addressing the first aim, tolerance to LBNP was not different between trials (P = 0.495). Decreases in systolic blood pressure from baseline to the end of LBNP also did not differ between trials (time P < 0.001, trial P = 0.477, interaction P = 0.587). Finally, increases in heart rate from baseline to the end of LBNP did not differ between trials (time P < 0.001, trial P = 0.626, interaction P = 0.424). Addressing the second aim, sufentanil attenuated perceived pain (P < 0.001) in response to the CPT, though the magnitude of the change in mean blood pressure during the CPT (P = 0.078) was not different between trials. These data demonstrate that sublingual sufentanil does not impair tolerance to progressive central hypovolemia. Additionally, sublingual sufentanil attenuates perceived pain, but not the accompanying mean blood pressure responses to the CPT.NEW & NOTEWORTHY Addressing two unique aims, we observed that sublingual sufentanil administration does not impair tolerance or cardiovascular responses to lower-body negative pressure (LBNP)-induced progressive central hypovolemia. Second, despite pain perception being reduced, sublingual sufentanil did not attenuate mean blood pressure responses to a cold pressor test (CPT).

"Peace of Mind" After Mastectomy: A Scoping Review.

BACKGROUND: Many women eligible for breast conservation therapy (BCT) elect unilateral mastectomy (UM) with or without contralateral prophylactic mastectomy (CPM) and cite a desire for "peace of mind." This study aimed to characterize how peace of mind is defined and measured and how it relates to surgical choice. METHODS: Nine databases were searched for relevant articles through 8 October 2023, and data were extracted from articles meeting the inclusion criteria. RESULTS: The inclusion criteria were met by 20 studies. Most were prospective cohort studies (65%, 13/20). In the majority of the studies (72%, 13/18), Non-Hispanic white/Caucasian women comprised 80 % or more of the study's sample. Almost half of the studies used the phrase "peace of mind" in their publication (45%, 9/20), and few directly defined the construct (15%, 3/20). Instead, words representing an absence of peace of mind were common, specifically, "anxiety" (85%, 17/20), "fear" (75%, 15/20), and "concern" (75%, 15/20). Most of the studies (90%, 18/20) measured peace of mind indirectly using questionnaires validated for anxiety, fear, worry, distress, or concern, which were administered at multiple postoperative time points (55%, 11/20). Most of the studies (95%, 18/19) reported at least one statistically significant result showing no difference in peace of mind between BCT, UM, and/or CPM at their latest time of assessment. CONCLUSION: Peace of mind is largely framed around concepts that suggest its absence, namely, anxiety, fear, and concern. Existing literature suggests that peace of mind does not differ among average-risk women undergoing BCT, UM, or CPM. Shared surgical decisions should emphasize at least comparable emotional and/or psychosocial well-being between CPM and breast conservation.

Risk of Serious Adverse Gastrointestinal Events with Potassium Binders in Hospitalized Patients: A National Study.

BACKGROUND: Concerns about serious adverse gastrointestinal (GI) events with sodium polystyrene sulfonate (SPS) led to development of two new potassium binders, patiromer and sodium zirconium cyclosilicate (SZC), for treatment of hyperkalemia. OBJECTIVE: To compare risk of intestinal ischemia/thrombosis or other serious GI events associated with SPS, patiromer, or SZC in hospitalized patients. DESIGN: Retrospective cohort study. PARTICIPANTS: National sample of 3,144,960 veterans hospitalized 2016-2022 in the U.S. Department of Veterans Affairs Healthcare System. MAIN MEASURES: Demographics, comorbidities, medications and outcomes were ascertained from the VA Corporate Data Warehouse. Exposures were SPS, patiromer, SZC. Outcomes were 30-day intestinal ischemia/thrombosis, and a composite of intestinal ischemia/thrombosis, peptic ulcer/perforation or bowel resection/ostomy. KEY RESULTS: Potassium binders were used during 39,270 (1.3%) hospitalizations: SPS = 30,040 (1.0%), patiromer = 3,750 (0.1%), and SZC = 5,520 (0.2%). Intestinal ischemia/thrombosis occurred with 106/30,040 (0.4%) SPS, 12/3750 (0.3%) patiromer and 24/5520 (0.4%) SZC, vs. 6998/3,105,650 (0.2%) without potassium binder. Adjusted odds ratios (aOR) were 1.40 [95% CI, 1.16 to 1.69] with SPS, 1.36 [CI, 0.79 to 2.36] with patiromer, and 1.78 [CI, 1.21 to 2.63] with SZC exposures. Composite GI adverse events occurred with 754/30,040 (2.5%) SPS, 96/3750 (2.6%) patiromer, 2.6% SZC, vs. 144/5520 (2.4%) without binder; aOR were 1.00 [CI, 0.94 to 1.08] with SPS, 1.08 [CI, 0.89 to 1.32] with patiromer, and 1.08 [CI, 0.93 to 1.27] with SZC exposures. No statistical difference in intestinal ischemia/thrombosis between each new agent and SPS was seen (p = 0.274 for SPS vs. SZC; p = 0.916 for SPS vs. patiromer). CONCLUSION: Risk of intestinal ischemia/thrombosis or other serious adverse GI events was low and did not differ across three potassium-binding drugs.

The impact of cannabis use disorder on urologic oncologic surgery morbidity, length of stay, and inpatient cost: analysis of the National Inpatient Sample from 2003 to 2014.

PURPOSE: This study examined the impact of cannabis use disorder (CUD) on inpatient morbidity, length of stay (LOS), and inpatient cost (IC) of patients undergoing urologic oncologic surgery. METHODS: The National Inpatient Sample (NIS) from 2003 to 2014 was analyzed for patients undergoing prostatectomy, nephrectomy, or cystectomy (n = 1,612,743). CUD was identified using ICD-9 codes. Complex-survey procedures were used to compare patients with and without CUD. Inpatient major complications, high LOS (4th quartile), and high IC (4th quartile) were examined as endpoints. Univariable and multivariable analysis (MVA) were performed to compare groups. RESULTS: The incidence of CUD increased from 51 per 100,000 admissions in 2003 to 383 per 100,000 in 2014 (p < 0.001). Overall, 3,503 admissions had CUD. Patients with CUD were more frequently younger (50 vs. 61), male (86% vs. 78.4%), Black (21.7% vs. 9.2%), and had 1st quartile income (36.1% vs. 20.6%); all p < 0.001. CUD had no impact on any complication rates (all p > 0.05). However, CUD patients had higher LOS (3 vs. 2 days; p < 0.001) and IC ($15,609 vs. $12,415; p < 0.001). On MVA, CUD was not an independent predictor of major complications (p = 0.6). Conversely, CUD was associated with high LOS (odds ratio (OR) 1.31; 95% CI 1.08-1.59) and high IC (OR 1.33; 95% CI 1.12-1.59), both p < 0.01. CONCLUSION: The incidence of CUD at the time of urologic oncologic surgery is increasing. Future research should look into the cause of our observed phenomena and how to decrease LOS and IC in CUD patients.

Identification of cellular and noncellular components of mature intact human peripheral nerve.

BACKGROUND AND AIMS: The goal of this study was to define basic constituents of the adult peripheral nervous system (PNS) using intact human nerve tissues. METHODS: We combined fluorescent and chromogenic immunostaining methods, myelin-selective fluorophores, and routine histological stains to identify common cellular and noncellular elements in aldehyde-fixed nerve tissue sections. We employed Schwann cell (SC)-specific markers, such as S100ß, NGFR, Sox10, and myelin protein zero (MPZ), together with axonal, extracellular matrix (collagen IV, laminin, fibronectin), and fibroblast markers to assess the SC's relationship to myelin sheaths, axons, other cell types, and the acellular environment. RESULTS: Whereas S100ß and Sox10 revealed mature SCs in the absence of other stains, discrimination between myelinating and non-myelinating (Remak) SCs required immunodetection of NGFR along with axonal and/or myelin markers. Surprisingly, our analysis of NGFR+ profiles uncovered the existence of at least 3 different novel populations of NGFR+/S100ß- cells, herein referred to as nonglial cells, residing in the stroma and perivascular areas of all nerve compartments. An important proportion of the nerve's cellular content, including circa 30% of endoneurial cells, consisted of heterogenous S100ß negative cells that were not associated with axons. Useful markers to identify the localization and diversity of nonglial cell types across different compartments were Thy1, CD34, SMA, and Glut1, a perineurial cell marker. INTERPRETATION: Our optimized methods revealed additional detailed information to update our understanding of the complexity and spatial orientation of PNS-resident cell types in humans.

Conditional survival does not improve over time in metastatic castration-resistant prostate cancer patients undergoing docetaxel.

PURPOSE: To investigate the conditional overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel chemotherapy. METHODS: We used deidentified patient-level data from the Prostate Cancer DREAM Challenge database and the control arm of the ENTHUSE 14 trial. We identified 2158 chemonaïve mCRPC patients undergoing docetaxel chemotherapy in the five randomized clinical trials. The 6-month conditional OS was calculated at times 0, 6, 12, 18, and 24 months from randomization. Survival curves of each group were compared using the log-rank test. Patients were then stratified into low- and high-risk groups based on the median predicted value of our recently published nomogram predicting OS in mCRPC patients. RESULTS: Nearly half (45%) of the study population was aged between 65 and 74 years. Median interquartile range prostate-specific antigen for the overall cohort was 83.2 (29.6-243) ng/mL, and 59% of patients had bone metastasis with or without lymph node involvement. The 6-month conditional survival rates at 0, 6, 12, 18, and 24 months for the entire cohort were 93% (95% confidence interval [CI]: 92-94), 82% (95% CI: 81-84), 76% (95% CI: 73-78), 75% (95% CI: 71-78), and 71% (95% CI: 65-76). These rates were, respectively, 96% (95% CI: 95-97), 92% (95% CI: 90-93), 84% (95% CI: 81-87), 81% (95% CI: 77-85), and 79% (95% CI: 72-84) in the low-risk group and 89% (95% CI: 87-91), 73% (95% CI: 70-76), 65% (95% CI: 60-69), 64% (95% CI: 58-70), and 58% (95% CI: 47-67) in the high-risk group. CONCLUSION: The conditional OS for patients undergoing docetaxel chemotherapy tends to plateau over time, with the main drop in conditional OS happening during the first year from initiating docetaxel treatment. That is the longer a patient survives, the more likely they are to survive further. This prognostic information could be a useful tool for a more accurate tailoring of both follow-up and therapies. PATIENT SUMMARY: In this report, we looked at the future survival in months of patients with metastatic castration resistant prostate cancer on chemotherapy who have already survived a certain period. We found that the longer time that a patient survives, the more likely they will continue to survive. We conclude that this information will help physicians tailor follow-ups and treatments for patients for a more accurate personalized medicine.

Time to second biochemical recurrence as a prognostic indicator in postprostatectomy patients who undergo salvage radiation therapy: An RTOG 9601 based post hoc analysis.

INTRODUCTION AND OBJECTIVE: The prognostic significance of a "second" biochemical recurrence (sBCR) after salvage radiation therapy (sRT) with/without hormonal therapy following primary radical prostatectomy in men with prostate cancer has not been examined. We hypothesized that a shorter time to sBCR will be associated with worse cancer control outcomes. METHODS: The RTOG 9601 study included 760 patients with tumor stage pT2/T3, pN0, who had either persistently elevated prostate-specific antigen (PSA) postradical prostatectomy or developed subsequent biochemical recurrence with PSA levels between 0.2 and 4.0 ng/ml. All patients received sRT (with or without 2 years of Bicalutamide) from 1998 to 2015. For our study, we focused on 421 patients who had sBCR after sRT-which was defined as a PSA increase of at least 0.3 ng/ml over the first nadir. Patients were divided into two categories: early sBCR (n = 210) and late sBCR (n = 211) using median time to sBCR (3.51 years). All patients who experienced sBCR received salvage hormonal therapy. Competing-risk analysis was used to examine the impact of early versus late sBCR on prostate cancer specific mortality (CSM), after accounting for available covariates. RESULTS: The majority of patients were age 60 years or older (75.8%), had pT3 disease (74.8%), and Gleason score 7 (75.2%). Overall, 13.8% had persistent PSA initially after surgery. At 10 years, starting at the time of sBCR, CSM rate was 31.3% in the early sBCR group versus 20.0% in the late sBCR group. In competing-risk analysis, time to sBCR was an independent predictor of CSM, where patients with early sBCR had 1.7-fold higher CSM risk (p = 0.026) than their counterparts with late sBCR. CONCLUSIONS: Time to sBCR after sRT (with or without concomitant Bicalutamide) is a significant predictor of CSM following initial radical prostatectomy. This information can be used to guide subsequent treatments, and to counsel patients.

Benefit of Extended Surveillance of Low-Risk Pancreatic Cysts After 5-Year Stability: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Low-risk branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) lacking worrisome features (WF) and high-risk stigmata (HRS) warrant surveillance. However, their optimal duration, especially among cysts with initial 5 years of size stability, warrants further investigation. We systematically reviewed the surveillance of low-risk BD-IPMNs and investigated the incidence of WF/HRS and advanced neoplasia, high-grade dysplasia, and pancreatic cancer during the initial (<5 years) and extended surveillance period (>5-years). METHODS: A systematic search (CRD42020117120) identified studies investigating long-term IPMN surveillance outcomes of low-risk IPMN among the Cochrane Library, Embase, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, from inception until July 9, 2021. The outcomes included the incidence of WF/HRS and advanced neoplasia, disease-specific mortality, and surveillance-related harm (expressed as percentage per patient-years). The meta-analysis relied on time-to-event plots and used a random-effects model. RESULTS: Forty-one eligible studies underwent systematic review, and 18 studies were meta-analyzed. The pooled incidence of WF/HRS among low-risk BD-IPMNs during initial and extended surveillance was 2.2% (95% CI, 1.0%-3.7%) and 2.9% (95% CI, 1.0%-5.7%) patient-years, respectively, whereas the incidence of advanced neoplasia was 0.6% (95% CI, 0.2%-1.00%) and 1.0% (95% CI, 0.6%-1.5%) patient-years, respectively. The pooled incidence of disease-specific mortality during initial and extended surveillance was 0.3% (95% CI, 0.1%-0.6%) and 0.6% (95% CI, 0.0%-1.6%) patient-years, respectively. Among BD-IPMNs with initial size stability, extended surveillance had a WF/HRS and advanced neoplasia incidence of 1.9% (95% CI, 1.2%-2.8%) and 0.2% (95% CI, 0.1%-0.5%) patient-years, respectively. CONCLUSIONS: A lower incidence of advanced neoplasia during extended surveillance among low-risk, stable-sized BD-IPMNs was a key finding of this study. However, the survival benefit of surveillance among this population warrants further exploration through high-quality studies before recommending surveillance cessation with certainty.

Estimated mortality with early empirical antibiotic coverage of methicillin-resistant Staphylococcus aureus in hospitalized patients with bacterial infections: a systematic review and meta-analysis.

OBJECTIVES: We performed a systematic review and meta-analysis to estimate the effect of early active empirical antibiotics for MRSA on mortality, both in patients admitted with MRSA infections and in patients admitted with common infectious syndromes, for whom the causative pathogen may not have been MRSA. METHODS: A systematic literature search was conducted using Embase, MEDLINE, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from the earliest entry through to 26 April 2022. We included studies of patients hospitalized with culture-proven MRSA infections that compared mortality rates depending on whether patients received active empirical antibiotics. The primary outcome was the adjusted OR for mortality with early active empirical antibiotics. After performing random-effects meta-analysis, we estimated the absolute risk reduction in mortality with initial empirical MRSA coverage for common infectious syndromes based on the prevalence of MRSA and baseline mortality rate for each syndrome, as reported in the medical literature. RESULTS: Of an initial 2136 unique manuscripts, 37 studies (11 661 participants) met our inclusion criteria. Fifteen studies (6066 participants) reported adjusted OR of mortality. The pooled adjusted OR for mortality was 0.64 (95% CI, 0.48-0.84), favouring active empirical antibiotics. The estimated absolute mortality benefit was 0% for patients with pneumonia, 0.1% (95% CI, 0.04-0.2) for non-critically ill patients with soft tissue infections, 0.04% (95% CI, 0.01-0.05) for non-critically ill patients with urinary tract infections, 0.6% (95% CI, 0.2-1.0) for patients with septic shock, and 1.0% (95% CI, 0.3-1.4) for patients with catheter-related infections admitted to ICUs. CONCLUSIONS: For the three most common infections in the hospital, the absolute benefit on mortality of empirical antibiotics against MRSA is 0.1% or less. Meaningful benefit of empirical antimicrobials against MRSA is limited to patients with approximately 30% mortality and 10% prevalence of MRSA. Avoiding empirical antibiotics against MRSA for low-risk infections would substantially reduce the use of anti-MRSA therapy.

Convolutional Neural Network Quantification of Gleason Pattern 4 and Association With Biochemical Recurrence in Intermediate-Grade Prostate Tumors.

Differential classification of prostate cancer grade group (GG) 2 and 3 tumors remains challenging, likely because of the subjective quantification of the percentage of Gleason pattern 4 (%GP4). Artificial intelligence assessment of %GP4 may improve its accuracy and reproducibility and provide information for prognosis prediction. To investigate this potential, a convolutional neural network (CNN) model was trained to objectively identify and quantify Gleason pattern (GP) 3 and 4 areas, estimate %GP4, and assess whether CNN-predicted %GP4 is associated with biochemical recurrence (BCR) risk in intermediate-risk GG 2 and 3 tumors. The study was conducted in a radical prostatectomy cohort (1999-2012) of African American men from the Henry Ford Health System (Detroit, Michigan). A CNN model that could discriminate 4 tissue types (stroma, benign glands, GP3 glands, and GP4 glands) was developed using histopathologic images containing GG 1 (n = 45) and 4 (n = 20) tumor foci. The CNN model was applied to GG 2 (n = 153) and 3 (n = 62) tumors for %GP4 estimation, and Cox proportional hazard modeling was used to assess the association of %GP4 and BCR, accounting for other clinicopathologic features including GG. The CNN model achieved an overall accuracy of 86% in distinguishing the 4 tissue types. Furthermore, CNN-predicted %GP4 was significantly higher in GG 3 than in GG 2 tumors (P = 7.2 × 10-11). %GP4 was associated with an increased risk of BCR (adjusted hazard ratio, 1.09 per 10% increase in %GP4; P = .010) in GG 2 and 3 tumors. Within GG 2 tumors specifically, %GP4 was more strongly associated with BCR (adjusted hazard ratio, 1.12; P = .006). Our findings demonstrate the feasibility of CNN-predicted %GP4 estimation, which is associated with BCR risk. This objective approach could be added to the standard pathologic assessment for patients with GG 2 and 3 tumors and act as a surrogate for specialist genitourinary pathologist evaluation when such consultation is not available.

Initial Management of Indeterminate Renal Lesions in a Statewide Collaborative: A MUSIC-KIDNEY Analysis.

PURPOSE: Renal masses can be characterized as "indeterminate" due to lack of differentiating imaging characteristics. Optimal management of indeterminate renal lesions remains nebulous and poorly defined. We assess management of indeterminate renal lesions within the MUSIC-KIDNEY (Michigan Urological Surgery Improvement Collaborative-Kidney mass: Identifying and Defining Necessary Evaluation and therapY) collaborative. MATERIALS AND METHODS: Each renal mass is classified as suspicious, benign, or indeterminate based on radiologist and urologist assessment. Objectives were to assess initial management of indeterminate renal lesions and the impact of additional imaging and biopsy on characterization prior to treatment. RESULTS: Of 2,109 patients, 444 (21.1%) had indeterminate renal lesions on their initial imaging, which included CT without contrast (36.2%), CT with contrast (54.1%), and MRI (9.7%). Eighty-nine patients (20.0%) underwent additional imaging within 90 days, 8.3% (37/444) underwent renal mass biopsy, and 3.6% (16/444) had reimaging and renal mass biopsy. Additional imaging reclassified 58.1% (61/105) of indeterminate renal lesions as suspicious and 21.0% (22/105) as benign, with only 20.9% (22/105) remaining indeterminate. Renal mass biopsy yielded a definitive diagnosis for 87%. Treatment was performed for 149 indeterminate renal lesions (33.6%), including 117 without reimaging and 123 without renal mass biopsy. At surgery for indeterminate renal lesions, benign pathology was more common in patients who did not have repeat imaging (9.9%) than in those who did (6.7%); for ≤4 cm indeterminate renal lesions, these rates were 11.8% and 4.3%. CONCLUSIONS: About 33% of patients diagnosed with an indeterminate renal lesion underwent immediate treatment without subsequent imaging or renal mass biopsy, with a 10% rate of nonmalignant pathology. This highlights a quality improvement opportunity for patients with cT1 renal masses: confirmation that the lesion is suspicious for renal cell carcinoma based on high-quality, multiphase, cross-sectional imaging and/or histopathological features prior to surgery, even if obtaining subsequent follow-up imaging and/or renal mass biopsy is necessary. When performed, these steps lead to reclassification in 79% and 87% of indeterminate renal lesions, respectively.

Nonsense-Mediated RNA Decay Factor UPF1 Is Critical for Posttranscriptional and Translational Gene Regulation in Arabidopsis.

Nonsense-mediated RNA decay (NMD) is an RNA control mechanism that has also been implicated in the broader regulation of gene expression. Nevertheless, a role for NMD in genome regulation has not yet been fully assessed, partially because NMD inactivation is lethal in many organisms. Here, we performed an in-depth comparative analysis of Arabidopsis (Arabidopsis thaliana) mutants lacking the NMD-related proteins UPF3, UPF1, and SMG7. We found different impacts of these proteins on NMD and the Arabidopsis transcriptome, with UPF1 having the biggest effect. Transcriptome assembly in UPF1-null plants revealed genome-wide changes in alternative splicing, suggesting that UPF1 functions in splicing. The inactivation of UPF1 led to translational repression, as manifested by a global shift in mRNAs from polysomes to monosomes and the downregulation of genes involved in translation and ribosome biogenesis. Despite these global changes, NMD targets and mRNAs expressed at low levels with short half-lives were enriched in the polysomes of upf1 mutants, indicating that UPF1/NMD suppresses the translation of aberrant RNAs. Particularly striking was an increase in the translation of TIR domain-containing, nucleotide binding, leucine-rich repeat (TNL) immune receptors. The regulation of TNLs via UPF1/NMD-mediated mRNA stability and translational derepression offers a dynamic mechanism for the rapid activation of TNLs in response to pathogen attack.

Discontinuation of Renin-Angiotensin-Aldosterone System Inhibitors Secondary to Hyperkalemia Translates into Higher Cardiorenal Outcomes.

INTRODUCTION: Discontinuation of renin-angiotensin-aldosterone system inhibitor (RAASi) is common after hyperkalemia. We evaluated the risk of kidney and mortality outcomes associated with RAASi discontinuation among patients with chronic kidney disease (CKD) and hyperkalemia. METHODS: We identified adult patients with CKD (eGFR <60 mL/min/1.73 m2) who experienced new-onset hyperkalemia (potassium ≥5.0 mEq/L) between 2016 and 2017 from Kaiser Permanente Southern California and followed them through 2019. We defined treatment discontinuation as having ≥90-day gap in refills of all RAASi within 3 months after hyperkalemia. We used multivariable Cox proportional hazards models to evaluate the association between RAASi discontinuation and the primary composite outcome of kidney (≥40% eGFR decline, dialysis, kidney transplant) or all-cause mortality. We evaluated cardiovascular events and recurrence of hyperkalemia as secondary outcomes. RESULTS: Among 5,728 patients (mean age 76 years), 13.5% discontinued RAASi within 3 months after new-onset hyperkalemia. During the median 2 years of follow-up, 29.7% had the primary composite outcome (15.5% with ≥40% eGFR decline, 2.8% dialysis or kidney transplant, 18.4% all-cause mortality). Patients who discontinued RAASi had a higher all-cause mortality compared with those who continued RAASi (26.7% vs. 17.1%) but had no differences in kidney outcomes, cardiovascular events, and recurrence of hyperkalemia. RAASi discontinuation was associated with a higher risk of kidney or all-cause mortality composite outcome (adjusted hazard ratio [aHR] 1.21, 95% CI: 1.06, 1.37) mainly driven by all-cause mortality (aHR: 1.34, 95% CI: 1.14, 1.56). CONCLUSION: RAASi discontinuation after hyperkalemia was associated with worsened mortality, which may underscore the benefits of continuing RAASi among patients with CKD.

Physiologic profile associated with severe multisystem inflammatory syndrome in children: a retrospective study.

OBJECTIVE: The purpose of this study was to describe the clinical presentation and physiologic profile of individuals with varying degrees of severity of multisystem inflammatory syndrome in children (MIS-C). METHODS: We performed a retrospective study of children diagnosed with MIS-C admitted to a single quaternary children's hospital from May 2020 to April 2021. We created an MIS-C severity score using the following parameters: hospital admission status (e.g., floor vs intensive care unit), need for inotropic or vasoactive medications, and need for mechanical ventilation. Univariate and multivariate analyses were performed to associate risk factors corresponding to the MIS-C severity score. RESULTS: The study included 152 children who were followed for 14 days post hospital admission. A stepwise forward selection process identified seven physiologic variables associated with "severe" MIS-C according to a logistic regression. Specifically, a combination of elevated creatinine (p = 0.013), international normalized ratio (p = 0.002), brain natriuretic peptide (p = 0.001), white blood cell count (p = 0.009), ferritin (p = 0.041), respiratory rate (p = 0.047), and decreased albumin (p = 0.047) led to an excellent discrimination between mild versus severe MIS-C (AUC = 0.915). CONCLUSION: This study derived a physiologic profile associated with the stratification of MIS-C severity. IMPACT: Based on a cohort of 152 individuals diagnosed with MIS-C, this study derived a nomenclature that stratifies the severity of MIS-C. Investigated demographic, presentational vital signs, and blood analytes associated with severity of illness. Identification of a multivariate physiologic profile that strongly associates with MIS-C severity. This model allows the care team to recognize patients likely to require a higher level of intensive care.

Impact of preexisting opioid dependence on morbidity, length of stay, and inpatient cost of urological oncological surgery.

OBJECTIVES: To determine the incidence of preexisting opioid dependence in patients undergoing elective urological oncological surgery. In addition, to quantify the impact of preexisting opioid dependence on outcomes and cost of common urologic oncological procedures at a national level in the USA. METHODS: We used the National Inpatient Sample (NIS) to study 1,609,948 admissions for elective partial/radical nephrectomy, radical prostatectomy, and cystectomy procedures. Trends of preexisting opioid dependence were studied over 2003-2014. We use multivariable-adjusted analysis to compare opioid-dependent patients to those without opioid dependence (reference group) in terms of outcomes, namely major complications, length of stay (LOS), and total cost. RESULTS: The incidence of opioid dependence steadily increased from 0.6 per 1000 patients in 2003 to 2 per 1000 in 2014. Opioid-dependent patients had a significantly higher rate of major complications (18 vs 10%; p < 0.001) and longer LOS (4 days (IQR 2-7) vs 2 days (IQR 1-4); p < 0.001), when compared to the non-opioid-dependent counterparts. Opioid dependence also increased the overall cost by 48% (adjusted median cost $18,290 [IQR 12,549-27,715] vs. $12,383 [IQR 9225-17,494] in non-opioid-dependent, p < 0.001). Multivariable analysis confirmed the independent association of preexisting opioid dependence with major complications, length of stay in 4th quartile, and total cost in 4th quartile. CONCLUSIONS: The incidence of preexisting opioid dependence before elective urological oncology is increasing and is associated with adverse outcomes after surgery. There is a need to further understand the challenges associated with opioid dependence before surgery and identify and optimize these patients to improve outcomes.

Preschoolers modulate contrastive inferences during online language comprehension.

This study examined 4- and 5-year-olds' incremental interpretation of size adjectives, focusing on whether contrastive inferences are modulated by speaker behavior. Children (N = 120, 59 females, mostly White, tested between July, 2018 and August, 2019) encountered either a conventional or unconventional speaker who labeled objects in a correspondingly typical or atypical way. Critical utterances contained size adjectives (e.g., "Look at the big duck"). With conventional speakers, gaze measures indicated that children rapidly used the adjective to differentiate members of a contrasting pair, indicating that even 4-year-olds derive contrastive inferences. With unconventional speakers, contrastive inferences were delayed in processing. The findings demonstrate that preschoolers adjust their use of pragmatic cues when presented with evidence disconfirming their default assumptions about a speaker.

Five-year-olds' sensitivity to knowledge discrepancies about object identity during online language comprehension.

In everyday communication, children experience situations where their knowledge or perspectives differ from those of their communicative partner. The current study examined this issue in the context of real-time language comprehension, focusing on 5-year-old children's ability to manage knowledge discrepancies about the identity of mutually visible objects. In Experiment 1, we examined 5-year-olds' ability to manage privileged knowledge about an object's identity. Using a referential communication task, we tested children (N = 60) in either a shared knowledge condition, where both the child and the speaker knew the identity of a visually misleading object (e.g., a candle that looks like an apple), or a privileged knowledge condition, where only the child knew the identity of the visually misleading object. Of interest was whether children could suppress private knowledge while processing a phonologically related word (e.g., "Look at the candy"). Results showed that children did not inhibit this knowledge during the early moments of referential interpretation. In Experiment 2 (N = 30), we contrasted the privileged knowledge condition in Experiment 1 with the more traditional scenario used to test common ground use, where the child knows the speaker cannot see certain display objects. Results confirmed a stronger ability to manage discrepancies in the latter case. Together, the findings demonstrate differences in children's ability to manage distinct types of knowledge discrepancies during real-time language comprehension.